1. Placebo response is not decreased by enrichment trial designs in randomized controlled trials of triptan medications in the paediatric age group
Lawrence Richer MD, MSc
4th International Clinical Trials Methodology Conference 2017
Liverpool, United Kingdom

2. Background
Migraine is a complex neurobiological disorder of recurring pain
Among most significant causes of neurological morbidity worldwide
Characterized by recurring moderate to severe headache with a pulsatile quality lasting hours and associated with nausea, vomiting, photophobia and sonophobia

3. Treatment Simple analgesics commonly used
Triptan medications (serotonin 1b/1d receptor agonists)
RCT evidence for efficacy in children or adolescents inconsistent
High placebo response is often implicated

4. Placebo response
Complex neurobiological response associated with treatment expectation
Mechanism? - activation of endogenous opioids, dopamine; cannabinoid receptors and genetic variants of COMT
Can minimize – in order to maximize differentiation of drug
Can maximize – in order to enhance clinical response

5. Objectives
Evaluate the overall placebo response and compare enrichment versus non-enrichment designs in RCTs of migraine treatment with any triptan medication among children or adolescents

6. Methods
Seven bibliographic databases, four clinical trial registers and grey literature searched through February 2016
All prospective RCTs of children and adolescents with migraine of symptom relieving drugs
Co-primary outcomes
Pain-free at 2 hours
Headache relief at 2 hours

7. Meta-analysis Average effect  weighted mean
Weights are the inverse variance of each study effect estimator
Larger studies and studies with less random variation given greater weight over smaller studies
Random effects model used

8. Results

9. Characteristics of included studies
25 randomized controlled trials (RCTs) of triptan medications in adolescents or children completed between 1992 and 2013
Adolescents and children were evaluated separately
Characteristic
N studies
Study design
Cross-over
Parallel 9 16
Age group
Adolescent
Child 22 3
Route
Oral
Intranasal 17 8
Sponsor
Pharmaceutical
Unclear/Investigator 20 5

10. Triptan medications included
Drug name
No enrichment
Enrichment
Total
Almotriptan 1
Eletriptan
Naratriptan
Rizatriptan 3 2 5
Sumatriptan 12
Sumatriptan/Naproxen
Zolmitriptan 4 20 25

11. Pain-free by Enrichment Design
20 studies
5 studies
N = 20 studies
N = 5 studies
N = 25 studies

12. Headache Relief by Enrichment Design
20 studies
5 studies

13. Placebo run-in (n=2 studies)

14. Non-responder (n=3 studies)

16. Performance of Enrichment Strategy
Placebo run-in (2 studies reporting)
478 excluded of 2518 enrolled (19%)
1 of 2 met primary objective re: efficacy
Non-responder (2 study reporting; one with two age groups)
100 excluded of 1382 enrolled (14%)
1 of 2 studies met primary objective re: efficacy

18. Subgroup and Sensitivity Analysis Pain-free
Characteristic
% (95% CI)
%(95% CI) p
Study Design
Cross-over
Parallel group
17% (14-21%)
22% (18-26%)
0.063
Age group
Adolescents (12-17 yrs)
Children (<12 yrs)
21% (17-24%)
26% (19-34%)
0.166
Route
Oral
Intranasal
21% (17-25%)
0.694
Sponsorship
Pharmaceutical
Unclear / Investigator
22% (19-26%)
19% (13-24%)
0.41

19. Placebo Response – Adult vs Pediatric
Cameron C, et al. Headache Jul;55 Suppl 4:221–35. 

20. Why is placebo response high?
Suggestibility due to younger age
Vigorous neurobiological response
Patient reported outcomes / pain

21. Conclusions
Placebo response is higher in pediatric RCTs of triptan medications
Enrichment designs as a group did not significantly decrease the placebo response
Significant variability between studies
Placebo run-in enrichment design may be a more effective strategy
Limited to two studies

22. Acknowledgements Lisa Hartling Ben Vandermeer Meghan Linsdell
Ellen Crumley
Lori Billinghurst
Kelly Russell
Ellen T Crumley
Tamara Durec
Terry P Klassen
Funding: Stollery Children’s Hospital Foundation